Identification of compensatory mechanisms to rescue aortic arch artery defects

确定挽救主动脉弓动脉缺损的代偿机制

基本信息

批准号：
10545745
负责人：
Sophie Astrof
金额：
$ 46.83万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-05 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10545745
关键词：
22q11 3-Dimensional Alleles Applications Grants Arteries Blood Blood Vessels Branchial arch structure Breathing Candidate Disease Gene Cardiovascular system Cells Chemotactic Factors Chromosome abnormality Circulation Compensation Congenital Abnormality Coupled DNA Sequence Alteration Data Defect Development DiGeorge Syndrome Diagnosis Eating Embryo Endothelial Cells Endothelium Ensure Etiology Fibroblast Growth Factor Fibronectins Fluorescent in Situ Hybridization Future Genes Genetic Engineering Goals Growth Factor Heart Human Hypoplastic Left Heart Syndrome Hypoxia Immunohistochemistry Impairment In Situ Hybridization Integrins Interruption KDR gene Knock-in Mouse Knowledge Lead Maps Mediating Modeling Morphogenesis Mouse Strains Mus Mutagenesis Mutate Neonatal Newborn Infant Pathogenicity Pathway interactions Patients Process Quality of life Route Signal Transduction Source Stromal Cell-Derived Factor 1 Syndrome Testing Trees Vascular Endothelial Growth Factors Veins Venous Work aortic arch confocal imaging congenital heart disorder dosage endothelial stem cell follow-up insight mouse development mouse model mutant mutant mouse model novel prevent progenitor prophylactic recruit repaired response transcription factor transcriptome sequencing

项目摘要

PROJECT SUMMARY The aortic arch artery and its branches are blood vessels that route the oxygenated blood from the heart to the systemic circulation. Defects in the development of the aortic arch artery lead to lethal forms of congenital heart disease (CHD) due to interruption(s) in the systemic circulation, for example, the interrupted aortic arch type B (IAA-B). These defects often occur in conjunction with 22q11 deletion syndrome, the most common congenital chromosomal abnormality syndrome in humans. Therefore, understanding genes and mechanisms regulating the development of the aortic arch artery will provide valuable insights into CHD etiology and potential treatments. Aortic arch artery and its branches form following the remodeling of the symmetrical pharyngeal arch arteries (PAAs) into the asymmetrical vascular tree. We demonstrated that the PAA endothelium is mainly derived from progenitors in the second heart field (SHF). Furthermore, we found that genetic mutations resulting in the deficiency in the SHF-derived endothelium cause IAA-B. This grant application describes two new mouse models in which an unexpected source of endothelial progenitors repairs the deficiency in the SHF- derived endothelial cells (ECs) and rescues aortic arch artery formation. Our discovery of an alternative endothelial source that repairs PAA defects has opened the possibility to determine mechanisms regulating this compensatory repair process. We also discovered that the compensatory endothelium is not recruited in the Tbx1+/- mouse model of 22q11 deletion syndrome, resulting in IAA-B and neonatal lethality in ~65% of Tbx1+/- mice. In this grant application, we propose to determine the source of compensating ECs, mechanisms regulating the recruitment of compensatory endothelium, and how Tbx1 regulates this process. To accomplish these goals, we propose the following Specific Aims: 1 To test the hypothesis that the compensating endothelium is derived from a vein, and 2 To determine signals regulating the recruitment of the compensatory ECs to rescue arch artery formation. In this proposal, we will use novel mouse strains, genetic engineering, quantitative 3D confocal imaging, in situ hybridization, and RNAseq to uncover candidate genes regulating the compensatory response. Upon completing the proposed work, we will uncover innate mechanisms of compensation and robustness, whereby a newborn's viability is ensured through alternative mechanisms. Harnessing these mechanisms would provide new opportunities for treatments of CHD in the future.

项目摘要主动脉弓动脉及其分支是输送含氧血液的血管从心脏到体循环。主动脉弓动脉发育缺陷导致致命形式由于体循环中断而引起的先天性心脏病 (CHD)，例如，血液循环中断 B 型主动脉弓 (IAA-B)。这些缺陷通常与 22q11 缺失综合征同时发生，这是最常见的人类常见的先天性染色体异常综合症。因此，了解基因和调节主动脉弓发育的机制将为冠心病病因学提供有价值的见解和潜在的治疗方法。主动脉弓及其分支是随着对称动脉的重塑而形成的。咽弓动脉（PAA）进入不对称血管树。我们证明 PAA 内皮细胞主要来源于第二心脏区域（SHF）的祖细胞。此外，我们还发现基因突变导致 SHF 衍生内皮细胞缺乏，导致 IAA-B。该拨款申请描述了两个新的小鼠模型中，意外来源的内皮祖细胞修复了 SHF- 的缺陷衍生内皮细胞（EC）并挽救主动脉弓动脉形成。我们发现了替代方案修复 PAA 缺陷的内皮源为确定调节 PAA 的机制提供了可能性补偿修复过程。我们还发现代偿性内皮细胞在 22q11 缺失综合征的 Tbx1+/- 小鼠模型，约 65% 的 Tbx1+/- 导致 IAA-B 和新生儿致死率老鼠。在本次拨款申请中，我们建议确定补偿性 EC 的来源、监管机制代偿性内皮细胞的募集，以及 Tbx1 如何调节这一过程。为了实现这些目标，我们提出以下具体目标： 1 检验补偿性内皮细胞衍生的假设 2 确定调节补偿性 EC 募集以拯救足弓的信号动脉形成。在本提案中，我们将使用新型小鼠品系、基因工程、定量 3D 共焦成像、原位杂交和 RNAseq 来发现调节补偿反应的候选基因。完成拟议的工作后，我们将揭示补偿和稳健性的内在机制，通过替代机制确保新生儿的生存能力。利用这些机制将为未来冠心病的治疗提供了新的机遇。